Department of Physics, and Center for Cellular and Biomolecular Machines, University of California, Merced, California, United States of America.
PLoS Comput Biol. 2022 Jun 8;18(6):e1010217. doi: 10.1371/journal.pcbi.1010217. eCollection 2022 Jun.
In cells, multiple molecular motors work together as teams to carry cargoes such as vesicles and organelles over long distances to their destinations by stepping along a network of cytoskeletal filaments. How motors that typically mechanically interfere with each other, work together as teams is unclear. Here we explored the possibility that purely physical mechanisms, such as cargo surface fluidity, may potentially enhance teamwork, both at the single motor and cargo level. To explore these mechanisms, we developed a three dimensional simulation of cargo transport along microtubules by teams of kinesin-1 motors. We accounted for cargo membrane fluidity by explicitly simulating the Brownian dynamics of motors on the cargo surface and considered both the load and ATP dependence of single motor functioning. Our simulations show that surface fluidity could lead to the reduction of negative mechanical interference between kinesins and enhanced load sharing thereby increasing the average duration of single motors on the filament. This, along with a cooperative increase in on-rates as more motors bind leads to enhanced collective processivity. At the cargo level, surface fluidity makes more motors available for binding, which can act synergistically with the above effects to further increase transport distances though this effect is significant only at low ATP or high motor density. Additionally, the fluid surface allows for the clustering of motors at a well defined location on the surface relative to the microtubule and the fluid-coupled motors can exert more collective force per motor against loads. Our work on understanding how teamwork arises in cargo-coupled motors allows us to connect single motor properties to overall transport, sheds new light on cellular processes, reconciles existing observations, encourages new experimental validation efforts and can also suggest new ways of improving the transport of artificial cargo powered by motor teams.
在细胞中，多个分子马达作为团队一起工作，通过沿着细胞骨架丝的网络步移，将货物（如囊泡和细胞器）长距离运输到它们的目的地。目前还不清楚，那些通常在机械上相互干扰的马达如何作为团队一起工作。在这里，我们探索了纯粹的物理机制（如货物表面流动性）是否可能增强团队合作的可能性，包括在单个马达和货物层面上。为了探索这些机制，我们开发了一个沿微管运输货物的三维模拟，该模拟由肌球蛋白-1 马达团队进行。我们通过显式模拟马达在货物表面上的布朗动力学来考虑货物膜流动性，并考虑了单个马达功能的负载和 ATP 依赖性。我们的模拟表明，表面流动性可能导致肌球蛋白之间的负机械干扰减少，并增强负载共享，从而增加单个马达在纤维上的平均持续时间。这一点，再加上更多的马达结合导致的结合速率的协同增加，从而提高了集体的连续性。在货物层面上，表面流动性使得更多的马达可用于结合，这可以与上述效应协同作用，进一步增加运输距离，尽管这种效应仅在低 ATP 或高马达密度时才显著。此外，流体表面允许马达在相对于微管的一个明确定义的位置聚集，并且流体耦合的马达可以对负载施加更多的集体力。我们对理解货物结合马达中团队合作如何产生的研究，使我们能够将单个马达的特性与整体运输联系起来，为细胞过程提供了新的认识，调和了现有的观察结果，鼓励了新的实验验证工作，并且还可以提出新的方法来改善由马达团队驱动的人工货物的运输。
